Dr. M. Edip Gurol is a Stroke Neurologist and early-career investigator at Massachusetts General Hospital, whose goal is to become an independent investigator with expertise in molecular and functional imaging of small vessel brain diseases in the elderly. Dr. Gurol's career development plan leverages the resources of a world-class environment by bringing together an outstanding team of investigators from Massachusetts General Hospital and Harvard Medical School at the forefront of the field of small vessel brain disease (SVD). Dr. Gurol has already obtained strong preliminary results demonstrating the feasibility of a research plan that uses molecular and functional imaging to study mechanisms of tissue injury in cerebral amyloid angiopathy (CAA) and hypertensive arteriolosclerosis. Under the mentorship of Dr. Steven M. Greenberg, and co-Mentors Dr. Keith Johnson, Dr. Bruce Rosen and Dr. Rebecca Betensky, Dr. Gurol proposes: 1) to determine whether the severity of vascular amyloid deposition is associated with novel markers of hemorrhagic and ischemic tissue injury in CAA, 2) to map functional measures of vascular physiology and analyze its association of with amyloid deposits, ischemic brain lesions and cognitive deficits in SVD, and 3) to determine whether SVD- related microlesions (microbleeds and microinfarcts) are associated with in situ molecular changes and cognitive deficits. The overall goal of this proposal is to elucidate molecular mechanisms that result in hemorrhagic and ischemic brain injury in CAA and arteriolosclerosis, major causes of intracerebral hemorrhage and vascular cognitive impairment. Bringing together cutting-edge technology and a team with internationally recognized expertise, this project will both advance our understanding of a rapidly growing cause of disability in the elderly and serve as a strong training vehicle for Dr. Gurol's development as an independent investigator. Successful completion of the proposed studies, in concert with a structured didactic curriculum, will provide Dr. Gurol with the skills that are essential for him to develop an independent career in SVD research at the cutting edge of science. Using results on imaging markers of disease severity and progression obtained from the proposed projects, the candidate anticipates preparing his first independent RO1 application to identify innovative methods for prevention and treatment of SVD-related brain damage and cognitive impairment.